An inhibitor of advanced glycation end product formation reduces N epsilon-(carboxymethyl)lysine accumulation in glomeruli of diabetic rats.
An inhibitor of advanced glycation end product formation reduces N epsilon-(carboxymethyl)lysine accumulation in glomeruli of diabetic rats.
复制标题
晚期糖基化终产物形成的抑制剂可减少糖尿病大鼠肾小球中 N ε-(羧甲基)赖氨酸的积累。
DOI：
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发表时间：
2003
影响因子：
13.2
通讯作者：
T. Niwa
中科院分区：
文献类型：
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作者：
Sakurako Nakamura;T. Tachikawa;K. Tobita;I. Aoyama;F. Takayama;A. Enomoto;T. Niwa
背景
晚期糖化抑制剂 OPB-9195 可延缓大冢朗-埃文斯德岛脂肪 (OLETF) 大鼠（一种非胰岛素依赖型糖尿病模型）肾病的进展。本研究的目的是从组织学角度评估 N(ε)-(羧甲基)赖氨酸 (CML) 在糖尿病肾病发展中的作用，并研究 OPB-9195 抑制 CML 积累是否与预防 OLETF 大鼠肾小球病变直接相关。
方法
收集 OLETF 和 Long-Evans Tokushima Otsuka 大鼠的血液和尿液样本后，分别在 7、20、50 和 68 周时获取其肾脏。从 24 周龄到实验结束，对大鼠施用 OPB-9195。根据间接免疫荧光技术，使用针对 CML 的单克隆抗体检测肾脏中的 CML。使用 NIH Image 软件（NIMH 研究服务部，贝塞斯达，马里兰州）测量 CML 阳性肾小球面积。使用点计数技术测量肾小球中的透明变性和/或硬化区域以及系膜和肾小球体积。
结果
肾小球中的 CML 阳性面积不仅与尿白蛋白排泄量密切相关（r = 0.912；P = 0.001），而且与系膜和透明变性和/或硬化病变的体积密切相关（分别为 r = 0.859；P = 0.0019 和 r = 0.833；P = 0.0027）。 OPB-9195 治疗减少了 CML 阳性面积并阻止了系膜体积的增加，68 周时肾小球体积没有显着变化。在 68 周龄时，四只大鼠中有三只接受 OPB-9195 治疗，透明变性和/或硬化病变的体积也有所减少。
结论
CML 是一种主要的晚期糖基化终产物，有助于糖尿病肾病的发展，OPB-9195 抑制其积累可改善 OLETF 大鼠的肾小球病变。
BACKGROUND
An inhibitor of advanced glycation, OPB-9195, retards the progression of nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus. The aim of this study is to evaluate histologically the role of N(epsilon)-(carboxymethyl)lysine (CML) in the development of diabetic nephropathy and investigate whether inhibition of CML accumulation by OPB-9195 is associated directly with the prevention of glomerular lesions in OLETF rats.
METHODS
Kidneys of OLETF and Long-Evans Tokushima Otsuka rats were obtained at ages 7, 20, 50, and 68 weeks after collecting their blood and urine samples. OPB-9195 had been administered to the rats from age 24 weeks to the end of the experiments. CML in kidneys was detected by using a monoclonal antibody against CML according to an indirect immunofluorescence technique. CML-positive glomerular area was measured using NIH Image software (Research Services Branch of NIMH, Bethesda, MD). Hyalinized and/or sclerotic areas in glomeruli and mesangial and glomerular volume were measured using a point-counting technique.
RESULTS
CML-positive area in glomeruli correlated closely not only with urinary albumin excretion (r = 0.912; P = 0.001), but also with volumes of mesangium and hyalinized and/or sclerotic lesions (r = 0.859; P = 0.0019 and r = 0.833; P = 0.0027, respectively). Treatment with OPB-9195 reduced CML-positive area and prevented the increase in mesangial volume, with no significant change in glomerular volume at age 68 weeks. The volume of hyalinized and/or sclerotic lesions also decreased by treatment with OPB-9195 in three of four rats at age 68 weeks.
CONCLUSION
CML is a major advanced glycation end product contributing to the development of diabetic nephropathy, and inhibition of its accumulation by OPB-9195 results in amelioration of glomerular lesions in OLETF rats.